Modulation of Reelin signaling by cyclin-dependent kinase 5
Modulation of Reelin signaling by cyclin-dependent kinase 5
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DOI：
10.1016/j.brainres.2006.01.121
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发表时间：
2007-04-06
期刊：
影响因子：
2.9
通讯作者：
Mikoshiba, Katsuhiko
中科院分区：
文献类型：
--
作者：
Ohshima, Toshio;Suzuki, Hiromi;Mikoshiba, Katsuhiko
Reelin信号传导和细胞周期蛋白依赖性激酶5（Cdk 5）都调节发育中大脑中的神经元定位。使用双转基因小鼠，我们以前已经表明，这两个信号通路位于平行的方式，并有遗传相互作用。Disabled-1（Dab 1）是一种衔接蛋白，介导Reelin信号传导，并在Reelin与其受体结合时发生酪氨酸磷酸化。Dab 1的几种异构体在胚胎小鼠脑中表达，并且p80 [Dab 1（S55）]是翻译的主要蛋白。在本研究中，我们研究了CdkS介导的Dab 1磷酸化是否调节Reelin信号。Cdk 5在其羧基末端区域的多个位点磷酸化p80 Dabl，并且通过Fyn酪氨酸激酶的p80 Dabl的酪氨酸磷酸化通过这种Cdk 5介导的体外磷酸化而减弱。酪氨酸磷酸化。在Cdk 5缺陷的神经元中，外源性Reelin诱导的p80 Dab 1的酪氨酸磷酸化增强，证实了Cdk 5介导的Ser/Thr磷酸化对p80 Dab 1的酪氨酸磷酸化的抑制作用。然而，另一种亚型p45 Dabl [Dabl（271）]在独特的羧基末端区域内的一个丝氨酸残基处被CdkS磷酸化，并且其丝氨酸磷酸化增强酪氨酸磷酸化。通过Fyn，并导致p45 Dabl的进行性降解。这些结果表明Cdk 5通过Ser/Thr磷酸化调节Reelin信号传导。Dabl以同种型特异性的方式不同。(c)2006 Elsevier B. V.保留所有权利。
The Reelin signaling and Cyclin-dependent kinase 5 (Cdk5) both regulate neuronal positioning in the developing brain. Using double-transgenic mice, we have previously shown that these two signaling pathways lie in parallel fashion and have a genetic interaction. Disabled-1 (Dab1), an adapter protein, mediates Reelin signaling and becomes tyrosine-phosphorylated on the binding of Reelin to its receptors. Several isoforms of Dab1 are expressed in embryonic mouse brain, and p80 [Dab1(S55)] is the major protein translated. In the present study, we investigated whether CdkS-mediated phosphorylation of Dab1 modulates Reelin signaling. Cdk5 phosphorylates p80 Dabl at multiple sites in its carboxyl terminal region, and tyrosine phosphorylation of p80 Dabl by Fyn tyrosine kinase is attenuated by this Cdk5-mediated phosphorylation in vitro. Tyrosine phosphorylation. of p80 Dab1 induced by exogenous Reelin is enhanced in Cdk5-deficient neurons, corroborating the inhibitory effect of Cdk5-mediated Ser/Thr phosphorylation on tyrosine phosphorylation of p80 Dabl. Another isoform, p45 Dabl [Dabl(271)], however, is phosphorylated by CdkS at one serine residue within a unique carboxyl-terminal region, and its serine phosphorylation enhances tyrosine phosphorylation. by Fyn and results in progressive degradation of p45 Dabl. These results indicate that Cdk5 modulates Reelin signaling through the Ser/Thr phosphorylation. of Dabl differently in an isoform-specific manner. (c) 2006 Elsevier B.V. All rights reserved.